PROTOCOL SUMMARY/ABSTRACT Coronary artery disease is the leading cause of death in Western society. Stents are implanted in 70-90% of the 1.3 million percutaneous coronary interventions performed annually in the USA, of which 20% involve bifurcations. Coronary bifurcations remain one of the most challenging lesion subsets in interventional cardiology, with a lower procedural success rate and increased rates of long-term adverse cardiac events, ranging between 15-20% at six months to one year post-intervention. Despite the great interest in this complex lesion subset, percutaneous treatment of coronary bifurcations is still a controversial subject and multiple technical strategies have been proposed. Fundamental mechanical disturbances within the stent appear to be major determinants of stent restenosis. No two bifurcations are identical, and no single treatment strategy exists that can be applied to every bifurcation. The most important issue in bifurcation interventions is selecting the most appropriate strategy for a specific bifurcation. Accordingly, we intend to investigate for the first time in human the role of fluid stresses on stent restenosis. We will use a validated subject-specific finite element analysis of arterial bifurcations rooted in clinical and experimental data to faithfully predict stent restenosis. The overall objective of this proposal is to use an individualized approach to identify the optimal bifurcation stenting technique for a specific bifurcation. Our central hypothesis is that subject-specific simulations of bifurcation stenting optimize the local biomechanical environment and reduces stent restenosis. Our proposal brings together extensive expertise, infrastructure and preliminary work in fluid and solid mechanics, computational simulations and vascular biology. These findings will establish clinically-relevant hypotheses that will serve as basis for our long term goal; a large, randomized controlled trial to show improved clinical outcomes with patient-specific bifurcation stenting strategies. The proposed research is an example of how precision medicine with pre-procedural planning can help optimize bifurcation stenting and improve clinical outcomes. Patient-specific computational stenting simulations may shift the management paradigm of coronary bifurcation interventions and provide a new dimension on how to improve the stenting and post-dilatation techniques.